Cocaine abuse is a public health problem reaching our young adults and even unborn children. Sigma (?) receptor antagonists can reduce the behavioral effects, rewarding properties and toxicity of cocaine. We propose to contribute to this emerging field by using radioligand binding techniques to measure the in vivo occupancy of cerebral ? 1 receptors of normal mice by cocaine, by compounds thought to have potential as anti-cocaine medications, and by novel ? receptor ligands identified "in-house." Next, we shall determine the ability of these ? 1 receptor antagonists to attenuate cocaine's psychomotor stimulant effects in mice. Our main goal is to investigate correlations of the ? 1 receptor occupancy measures with attenuation of psychomotor stimulant effects. Promising ligands would advance to testing in reward models beyond the scope of this application. We have identified novel radioiodinated ligands that label ? 1 receptors in the brain and periphery of mice with a high level of specific binding and excellent metabolic stability. A surprisingly potent 68 [unreadable]mol / kg ED50 for cocaine occupancy of cerebral ? 1 receptors has been determined. Investigations of ? 1 receptor ligands as potential medications for cocaine abuse now rely only upon correlations of ligand affinity in vitro with the behavioral observations. Thus, a validated occupancy paradigm would fill a sizeable gap in the screening process. Moreover, using I-123 labeled radioligands, we propose to establish mouse SPECT as a means for non-invasive, longitudinal monitoring of ? 1 receptor occupancy that might be translated to the clinic. The innovation in our approach is three-fold: 1) we shall provide new insight into the contributions of ? 1 receptor occupancy to cocaine's behavioral effects;2) we shall establish a useful new paradigm that can help us and others screen potential ? 1 receptor-based anti- cocaine medications in vivo;and 3) we shall examine SPECT imaging as a technique for longitudinal monitoring of ? 1 receptor occupancy in vivo. The overall impact of our work would be the development of new techniques to assess the utility of pharmacological interventions involving ? 1 receptor ligands as one treatment avenue that could help release individuals from crippling dependence on cocaine and psychostimulant drugs of abuse. PUBLIC HEALTH RELEVANCE: Cocaine abuse is a serious public health issue with far reaching consequences. At present, there are no accepted medications to fight cocaine abuse. We are proposing laboratory studies of compounds that target special proteins, called sigma receptors, that are involved in cocaine's addictive power. Our goals are to gain a better understanding of cocaine's actions, to identify ways to screen anti- cocaine drug candidates in the laboratory, and possibly to translate the findings to the clinic.